189. Ca/PTH/Bone Basic Flashcards
Ca Homeostasis
- what is the fx of Ca in body
- how is Ca regulated
- how is Ca distributed in blood?
- brief sx of hypoCa and hyperCa
Fx: mLc: regulate excitable tissue, signal transduction, coagulation, enzyme activity, secretion; formation and maintenance of skeleton
Regulation: PTH tight feedback control keeps Ca b/w 8.5-10.4; low Ca = huge increase in PTH to restabilize Ca
Distribution: 50% ionized (active), 40% protein-bound (most albumin), 10% complexed with anions (PO4, citrate)
HypoCa: increased neuromuscular excitability
HyperCa: dehydration, renal stones, pain, weakness, confusion, arrhythmia
What 3 organs handle Ca and how do they regulate serum Ca levels?
How do certain meds change Ca absorption/excretion?
- Intestine: only 10-20% dietary Ca absorbed, promoted by diffusion thru small intestine and vit D dependent transport of Ca and PO4
lose gut Ca absorption due to GC use, mucosal/biliary secretion, malabsorption - Kidney: increase Ca reabsorption via PTH on distal nephron; increase Ca excretion via Loop Diuretics (thiazides decrease Ca excretion), high dietary protein, GC use
- Bone - major Ca storage as hydroxyapatite, >99% in stable pool, <1% in exchangeable pool, used for Ca homeostasis, buffering, structural skeleton (support body and protect internal organs), modulate bone marrow development (hematopoiesis, bone cell precursors, cytokines)
Appendicular bone - forearm, cortical bone
Axial bone - trabecular (vertebrae), highest activity and turnover
What are the three types of bone cells, their actions, and their secretions?
- Osteoclasts: multi-nucleated cells
Secrete: H+ and proteolytic enzymes to digest old/weak bone
RANKL: secreted by osteoblasts to membrane-assoc. cytokine receptor on osteoclast and clast precursors = STIM CLAST DEVELOPMENT: bind RANK - promote fusion differentiation activity and clast survival - Osteoblasts
Secrete: collagin (90% protein in bone matrix osteoid), markers of blast activity (alk phos, osteocalcin, collagen peptide cleavage fragments), cytokines (IL6), RANKL (stim clasts), osteoprotegerin (RANKL antagonist!)
Arise from: pluripotent precursors (give rise to adipocytes, chondrocytes, myocytes)
Promoted by Wnt Signaling, IGF1, bone morphogenic proteins
Mature to OSTEOCYTES - Osteocytes: 90% all bone cells, sense mechanical load
Secrete: SCLEROSTIN - inhibits Wnt Signaling = blocks blasts (sclerostin antagonists promote bone formation)
Vitamin D
- forms
- synthesis (stimulation for synthesis)
- actions
- effects of excess vit D
- tx uses
- analogues (names, use)
D2: plants/fungi, need prescription
D3: animals, avail OTC
Synthesis: 7-dehydrochol activated by UV light in skin, liver converts to 25-OH D, kidney activates to 1,25 di-OH D
PTH and low serum PO4 stim vit D activation in kidney
Actions: effects thru NUCLEAR RECEPTOR
- intestine: increase Ca/PO4 absorption (help increase bone mineralization)
- suppress PTH secretion (-fb)
Excess: hyperCa (via more Ca/PO4 absorption), direct action on osteoblasts to increase RANKL = more clast activity
Tx: Nutritional Rickets (Vit D deficiency)
Rickets + Osteomalacia due to inadequate 1-hydroxylation of 25-OH-D (VDRR, renal disease, hypoparathyroidism - no stim)
Adjunct for osteoporosis tx
ALPHACALCIDOL - 1-OH-D: does not require 1a-hydroxylase activity - useful for VDRR
PARACALCITOL: suppresses PTH, minimal intestine effects (reduce hyperCa SE), useful for secondary hyperPTH!
PTH
- structure/secretions
- mechanism and feedback
- antagonists (name, mechanism, route, use, SE)
- agonists (name, mechanism, route, use, SE)
84AA peptide secreted partially pulsatile
Mech: acts thru GPCRs in bone and kidney (stim PKA and PKC)
Kidney - increase Ca reabs, decrease PO4 reabs, stim 1a-hydroxylase to activate vit D
Intestine - indirect thru increasing vit D
Bone - continuous exposure (increase RANKL = increase bone resorption) vs intermittent exposure (block blast apoptosis, increase differentiation, decrease sclerostin production = increase bone formation)
Feedback: high Ca binds CaSR on parathyroid (GPCR) - adjusts PTH secretion based on amount Ca sensed
Antagonists: calcitriol and analogs - inhibit PTH secretion
Calcimimetics - BLOCK PTH
ex: CINACALCET: allosteric activator of CaSR (binds diff site than Ca), enhances sensitivity of CaSR (lowers [Ca] at which PTH is suppressed = decreases PTH sooner)
Use: suppress excess PTH in hyperPTH/PTH ca.
Kinetics: ORAL, CYP metabolism/renal excretion
SE: hypoCa -> adynamic bone disease (slows bone turnover)
Agonists:
Teriparatide (PTH 1-34): full PTH agonism
- use: anabolic agent for osteoporosis tx (intermittent exposure)
- route: sc injection
- SE: hyperCa, high incidence osteosarcoma (increased bone activity)
PTHrp: produced by many tissues
- hyperCa of malignancy (cancer), osteolytic mets of breast cancer, causes bone anabolism
ABALOPARATIDE: PTHrp analog: anabolic agent for osteoporosis
Calcitonin
- structure
- stimulation for secretion
- action
- tx use
32AA peptide secreted by thyroid C cells
Stim by high Ca
Acts on osteoclast GPCRs to inhibit bone resorption (anti-resorptive)
Use: Tx Paget’s disease, some hyperCa conditions (antiresorptive), minor drug for osteoporosis (low efficacy)
FGF-23
- structure, location
- action
- consequences of low and high levels FGF23
251AA peptide produced by osteoclasts and blasts
Stim by high calcitriol and phosphate
Action: decrease vit D synthesis in kidney, decrease PO4 reabsorption
Low FGF = tumor calcinosis
High FGF = high PO4 excretion = hypophosphatemic rickets
Estrogen
- fx
- actions
- use
- how do males have similar effect?
- SERMs - what are they, name, use, SE
- bone maintenance (menopause - lose E = accelerated bone loss)
- actions: antiresorptive + anabolic
Less production of RANKL and IL6
More production of osteoprotegerin (anti-RANKL)
More apoptosis of osteoclasts
Less sclerostin = promote osteoblast formation
Use: may prevent+tx postmenopausal osteoporosis (no longer used, assoc w/ heart disease and breast cancer)
Males: androges aromatized to estrogen in bone and act on receptors
SERMs: Selective estrogen receptor modulators
RALOXIFENE - interact on E receptors in tissue specific manner
bone: anti-resorptive (E AGONISM)
mammary gland: E-ANTAGONISM (decrease breast cancer risk)
Use: prevent + tx postmenopausal osteoporosis and decrease risk of breast cancer
SE: thromboses (E agonism), hot flashes (E antagonism), contraindicated in women who may become pregnant
Bisphosphonates
- what are they (names)
- mechanism
- use
- kinetics
- SE
Analogs of pyrophosphate (ALEDRONATE, RISEDRONATE, ZOLEDRONIC ACID, IBANDRONATE)
Mech: accumulate in bone at sites of active resorption - taken up by osteoclasts = inhibit osteoclast activity (anti-resorptive)
Use: prevent + tx osteoporosis, tx hyperCa, tx Paget’s disease, Tx bone mets from breast/prostate cancer
Kinetics: CANNOT TAKE WITH FOOD (poor oral absorption), super long half life (6-10years), dosed 1/wk or 1/mo, renal excretion
SE: GI (heartburn, esophagitis, abd pain, diarrhea)
osteonecrosis of jaw (poor mandible healing after dental procedure)
Atypical femoral fractures (spontaneous in mid-femur)
Denosumab
- what is it
- fx
- use
- SE
Human mAb against RANKL
Inhibits osteoclast fusion, fx, survival (anti-resorptive)
Increase BMD and decrease fracture risk
Use: tx osteoporosis (sc injection 1x/6mo), bone mets from solid tumors
SE: hypoCa, rashes, osteonecrosis of jaw, high infection risk in people with weak immune systems
Short-term and long-term effects of GCs on bone
Short-term: hypoCa via negative Ca balance (decreased Ca absorption and increased Ca excretion)
Long-term: Osteoporosis via negative Ca balance, increased PTH secretion, decreased gonadal steroids (decreased pit release of FSH/LH), decreased protein synthesis in bone
REVIEW
- what are the tx plans for hypoCa and hyperCa?
- what are the two tx plans for osteoporosis? When to use either one? meds for each.
HypoCa: Vit D, Calcitriol, Alphacalcidol, Thiazide Diuretics
HyperCa: Loop Diuretics, GCs, Bisphosphonates + Calcitonin (anti-resorptive)
Anabolic tx: useful when already below fracture threshold
- Teriparatide
- Abalaparatide
Anti-resorptive tx: useful EARLY to slow decline
- Bisphosphonates
- SERMs (raloxifine)
- Denosumab
- Estrogen
- Calcitonin
